16 September 2022

Aging and proteins

Protein clots associated with Alzheimer's disease affect the aging of all cells

Viviane Callier, Quanta Magazine: Protein Blobs Linked to Alzheimer’s Affect Aging in All Cells

Translated by Alexander Gorlov, XX2 century

The aging brain of people with Alzheimer's and Parkinson's diseases, as well as other neurodegenerative diseases, is replete with characteristic accumulations of proteins in or around neurons. How protein clots can harm neurons is still unclear in most cases, but these clots are the hallmarks of these diseases — and so far they have been associated almost exclusively with an aged brain.

However, the results of a recent study conducted by a group of scientists at Stanford University suggest that, apparently, protein aggregation in aging cells is a universal phenomenon and that it can be observed in more diseases of aging than is commonly believed. This discovery requires a new look at the negative processes occurring in cells as they age, and possibly indicates new ways to prevent some of the undesirable consequences of the aging process.

"This is a widespread phenomenon — not a single specific tissue, but many different tissues," says Della David, who was not involved in this study (Della David), an expert on aging processes from the Babraham Institute in Cambridge, England.

In addition, according to this study, protein aggregation is closely related to the main mechanisms by which cells regulate their physiological properties extremely delicately. Biologists will need to carefully find out, perhaps for each specific case, what protein clusters represent — a threat to cells or the protection they have created.

An article with the results of this study published in March on the preprint server biorxiv.org (Chen et al., Tissue-specific landscape of protein aggregation and quality control in an aging vertebra), represents the first attempt to quantify the degree of protein aggregation throughout the body during the natural aging of a vertebrate animal — in this case, a fish with a very short lifespan. The study showed that, probably, the aggregation of proteins over time contributes to the gradual deterioration of many tissues. Based on the results obtained, one can even assume for what reason these accumulations are much more noticeable in the brain than in other tissues: perhaps this is due to its faster development.

Dan Jarosz, a systems biologist from Stanford, who observed the progress of these experiments with his colleague, a geneticist By Anne Brunet, I did not expect that so many proteins accumulate in aging fish — and that very often these same proteins in mutant forms are associated with degenerative diseases. "This made me wonder if protein aggregation occurs in many other age—related diseases that are not currently associated with it," he said.

Tips from fish

The African Furzer's notobranch (Nothobranchius furzeri) lives in temporary ponds in East Africa formed during the rainy season. As this fish approaches the end of its 4-6-month life, it develops a number of age-related diseases, including cataracts and brain-related changes that resemble such a human neurodegenerative disorder as Alzheimer's disease. The notobranch's short lifespan — much shorter, for example, than that of a laboratory mouse — and rapid natural aging make it an ideal model for studying vertebrate aging.

"What is striking about this fish is that when it ages, not only protein aggregation, heart failure or brain dysfunction take place," says an expert on aging processes, an evolutionary biologist Dario Valenzano from the Max Planck Institute and the Leibniz Institute, Germany, who completed postdoctoral studies with Brunet. "Almost any organ and any tissue that we observe undergoes some downright catastrophic transformations during aging."


The African Furzer's notobranch is a vertebrate with an extremely short lifespan, only 4 to 6 months. As he moves from youth (above) to aging (below), he develops many health problems associated with old age in people.

The Stanford team conducted an extensive analysis of notobranch proteins at various stages of its youth and maturity. In the aging notobranch, scientists found protein accumulations in all the tissues they examined: not only in the brain, but also in the heart, intestines, liver, muscles, skin and testes. More than half of the accumulating proteins showed in further experiments a tendency to aggregation, which apparently has an innate character.

But exactly which proteins stuck together, forming clusters, turned out to be significantly different in different tissues. In several tissues, the expression of many proteins occurred, in fact, at equivalent levels, but if proteins accumulated in some tissues, then no protein adhesion occurred in others.

"The degree of tissue specificity of the accumulating proteome is amazing," says David. She and other researchers believe that these differences are based on how cells maintain the quality of their proteins. Cells have a complex mechanism for controlling the correct folding of the long chain peptide molecules that make up proteins, and even controlling that eventually these chains break down for recycling. However, Yarosh notes, tissues may depend differently on various aspects of the protein quality control process, and these accents may change with age.

"This is a very important topic, because the reason why neurodegenerative diseases manifest themselves very specifically in different tissues is a huge white spot in human biology," says Stanford University, who was not involved in the study Cynthia Kenyon, vice president of the biotechnology company Calico Life Sciences for the study of aging. And in fact: no one knows, for example, why amyloid protein plaques in Alzheimer's disease are formed in the hippocampus of the brain, and protein clusters in Parkinson's disease are specific to dopamine neurons. It is possible that different cells maintain the quality of their proteins in different ways. This, Kenyon believes, is "at least a very plausible explanation of why different tissues behave very differently."

The importance of quality control

Studies of worms and flies have convincingly shown that when the mechanism that ensures the stability of proteins fails, animals age faster. With the genetic improvement of ways to control the quality of proteins, animals tend to live longer. All this does not mean that protein aggregation causes aging, but clearly indicates a close relationship between these phenomena.

To further investigate the relationship between protein aggregation and aging, Stanford researchers took a closer look at the proteins of the mutant notobranch variety, which ages unusually quickly. These fish have a mutation in the telomerase gene that monitors the preservation of the length of dividing chromosomes; animals with telomerase mutations usually age quickly.

According to Yarosh, he and his colleagues expected to find fewer protein clusters in the intestine and other fast-growing or rapidly transforming tissues, since extraordinary cell division gives such tissues more opportunities to remove clusters and restore themselves. But the opposite is also true: such tissues contain more improperly folded and clumped proteins and age faster than tissues that grow slowly.

Again, problems with cellular quality control of proteins can serve as a good explanation. If cells lose control of the processes that maintain the quality of their proteins, with each cell division, the number of damages caused by protein clusters may increase. Tissues that grow rapidly can age rapidly due to the fact that they create favorable conditions for the accumulation of this harm.

Condensation, aggregation and prions

Why proteins sometimes accumulate is difficult to explain. To the surprise of scientists, it turned out that a partial explanation is provided by condensation — an important mechanism of cellular control over proteins.

The complex three-dimensional shapes that arise during the folding of peptides have historically been considered to determine the activity and functions of the proteins included in these structures. But over the past decade or so, it has been discovered that a growing list of proteins has an "internally disordered" region that is unable to fold into a stable form. Under the right conditions, a lot of these proteins are collected in droplets, or condensates, — a reversible process similar to "phase separation", in which oil droplets are formed in water. This process can enhance the activity of enzymes by concentrating them together with their substrates, or suppress this activity by isolating enzymes from their substrates. Cells, by changing the local concentration of substrates and enzymes within themselves, are able to use condensates to fine-tune their protein activity.

However, in addition, protein disordered regions can lead to more solid accumulations of proteins, hampering the work of cells and causing damage to them. Worse, some defective proteins not only fold incorrectly and form harmful clusters themselves, but also cause other proteins of the same type to fold incorrectly, which leads to a chain reaction of harmful accumulation. Conceptually, this is similar to what happens in "mad cow disease" and one of the variants of Creutzfeldt—Jakob syndrome, in which abnormally folded proteins called prions catalyze a wave of abnormal protein aggregation in the brain.

Thus, condensation is a control mechanism that involves certain risks. But, from the point of view of evolution, its advantages seem to be so significant that the price - vulnerability to many diseases associated with aging — seems to be worth paying, Yarosh notes.

A vivid illustration of this is provided by the second preprint published by the Stanford team in March (Harel et al., Identification of protein aggregates in the aging vertebrate brain with prion-like and phase separation properties). Here, the researchers focused on a protein called DDX5, which accumulates in the aging brain of Notobranch. DDX5, the most active in its condensed state, performs many important functions in the body, often helping it to determine whether other proteins are produced properly. Based on the amino acid sequence of DDX5, scientists predicted that its behavior would be prion, and later their prediction was confirmed: one incorrectly folded DDX5 protein contributes to the incorrect folding and aggregation of other DDX5 molecules.

However, aggregation does not end there: Stanford researchers found other proteins in the DDX5 clots. Clusters can sometimes act as "sticky clots" that capture other proteins, randomly interfering with cellular functions, explained John Labbadia, whose laboratory in University College London studies protein quality control and aging.

"This suggests that we have ... proteins that accumulate with age and are able to catalyze further protein aggregation in a prion—like manner, which has not been previously recorded," he said.


The Stanford team carefully identified the area of the DDX5 protein through which condensation controls its activity — and it turned out that this is the same area that also makes it prone to accumulation. Control over the natural function of a protein and its tendency to aggregation are inextricably linked. "It's a Catch-22," Labbadia said.

"In my opinion," Yarosh believes, "there has been a very interesting shift in the understanding of this topic: for an activity, if we take it in a very narrow sense, an unordered domain is not required, but, from the point of view of the actual deployment of this activity in a living system, it turned out that it actually plays an extremely important role." role".

Pathology or protection?

What exactly causes the formation of clusters and how harmful they are to cells remains, as Kenyon notes, "a difficult, fantastic, huge problem in this field of research." On the one hand, clusters bind DDX5 and other proteins, effectively preventing the implementation of important cellular functions. But, in addition, clusters are able to help cells survive, providing a protective effect.

A good example of a protective effect was the study of huntingtin, a protein that is most represented in the brain. Huntingtin is essential for the healthy development of the nervous system, but in people with Huntington's disease, a mutation of this protein causes it to become abnormally long. Then this long protein breaks down into short toxic segments that cause damage to the nervous system.

In 2004 Steve Finkbeiner, aging researcher at the Gladstone Institutes and the University of California at San Francisco (University of California, San Francisco), studied the aggregation of the huntingtin protein in cultured neurons. His team showed that although all neurons expressing the abnormal huntingtin protein die over time, neurons that have clusters of huntingtin live longer than those that do not.

"This was the first proof that the formation of [clusters] is a protective reaction to other submicroscopic forms of improperly folded proteins causing problems," Finkbeiner explained to the editorial board of Quanta magazine in an email.

Since then, he and other scientists have shown that the protective reaction of accumulation occurs in other neurodegenerative diseases. According to Finkbeiner, this may explain why attempts to treat Alzheimer's disease by targeting plaques have failed: if the amyloid plaques characteristic of this disease are formed to defensively bind the defective protein, then the destruction of plaques can do more harm than good.

"It's hard for people to understand this concept because common sense says that things that look abnormal should be 'bad' and pathogenic," Finkbeiner wrote. "But biology is complicated, it has a lot of feedback loops, so in order not to get into a mess, it's important not to jump to conclusions."

A universal problem with multiple solutions

Here is a picture that is clearly emerging at the present time: protein aggregation is a phenomenon not limited to neurodegenerative diseases. It is a part of the life of any cell capable of aging. Many normal proteins important for development, such as DDX5, tend to aggregate, and the fight against this adhesion is a universal task facing all cells.

Since this cellular problem is very old, it is possible that the prevention of aggregation acted as the main driving force of the evolution of protein sequences. Since abundantly presented proteins are prone to aggregation, and mutations reinforce this tendency, natural antimutation selection in abundant proteins is probably performed very rigidly. (This assumption is supported by the fact that in young animals, abundantly presented proteins tend to have a lower mutation rate). Thus, deficient proteins can evolve faster than abundant proteins, and a higher rate of evolution should correlate with the tendency to aggregation.

Brunet and Yarosh noticed that this effect is very vividly represented in the brain of Notobranch. Researchers have suggested that accumulating abundant proteins are key to innovative shifts in this organ. If this is the case, then the evolutionary changes in the brain that made it an extremely important organ of vertebrates may have made it more vulnerable to degenerative diseases caused by aggregation.

And indeed: it is quite likely, says Yarosh, that every tissue and every organ must find its own balance or compromise between doing its job and managing protein aggregation. Each tissue has unique functional requirements and limitations that it must obey: intestinal cells are constantly being updated; endocrine cells produce and secrete hormones; immune cells, having detected invaders, rush into battle; the brain processes information. Different proteins are required for different jobs, which means that the evolutionary strategies for combating protein aggregation could not but vary from tissue to tissue and from animal to animal. Since the vertebrate brain has evolved much more intensively and faster in the relatively recent past than, say, muscles, its protein quality control mechanism may not have had time to develop adequate protection against aggregation of relatively new proteins yet.

Nevertheless, the fundamental problem of protein aggregation exists for all organisms all the time, and not only during breaks between diseases and severe stressful conditions. Prion-like DDX5 and similar proteins, says David, "have an innate tendency to aggregation, and the body seeks to protect itself from it. This is a physiological phenomenon that we all have to take into account."

And the fact that the accumulation of proteins in all organs is a factor in the aging of such diverse organisms as yeast, worms, flies, fish, mice and humans, she added, "means that biologists should pay much more attention to this topic."

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